Könshormoners inverkan på minne och inlärning

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1 Könshormoners inverkan på minne och inlärning Torbjörn Bäckström Umeå Neurosteroid Research Center, Institutionen för Klinisk Vetenskap, Obstetrik och Gynekologi, Kvinnokliniken, Norrlands Universitets sjukhus, Umeå. Ekonomiskt stöd: EU mål 1, Vetenskapsrådet, Medicin, Västerbottens Landsting, Umeå Kommun, Norra sjukvårdsregionen, Visare Norr Umeå Universitets fonder

2 Bakgrunden till Womens Helth Initiative Memory Study (WHIMS) studien Epidemiologiska studier och mindre studier visade att estrogen förbättrar minnet och förhindrar demens Fedor-Freybergh 1977, Sherwin 1988, Phillips & Sherwin 1991, Duka 2000 Paganini-Hill & Henderson 1994, 1996 Baldereschi et al 1998 LeBlanc et al. Meta analysis. JAMA. 2001;285: Experimentell studie visade att estrogen förstärker verbalt minne minskar rumsligt minne Sherwin 1994, Drake 2000 Experimentell studie visade att medicinsk oophorectomi (GnRH-agonist) försämrar minnet, estrogen ad back återställer minnet Sherwin & Tulandi 1996

3 Case - Control studier visade profylaktiska effekter av estrogen behandling mot demens Estrogen replacement therapy and risk of Alzheimer disease. Paganini-Hill & Henderson Arch Intern Med. 1996;156:

4 WHIMS studien visade motsatt effekt med mer demens i estrogen + progestagen gruppen. Shumaker et al (2003) Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women: The Women's Health Initiative Memory Study: A Randomized Controlled Trial. JAMA 289, Participants ; Observation time 4.05 (1.19) years 2229 received mg CEE mg MedroxyProgesteroneAcetate (MPA); 2303 placebo. Diagnosed dementia, 40 (66%) in CEE + MPA; 21 (34%) in placebo. Hazard ratio 2.05 (95% CI, ; P =.01). This results in additional 23 cases of dementia per women per year. Alzheimer disease was the most common classification of dementia.

5 Probable dementia in postmenopausal women taking continuous HRT CEE mg + Medroxyprogesterone - acetate 2.5 mg or placebo Participants E+P Placebo Number Age % 45% % 35% >= 75 20% 21% Shumaker et al JAMA 289, (2003), Cumulative Hazard Probable Dementia HR 2.05, 95% CI Estrogen + Progestin Placebo Years Since Randomization

6 Estrogen ensam visar ingen signifikant ökning i demens men ej heller någon minskning. Probable dementia in hysterectomized postmenopausal women taking continuous CEE mg or placebo Participants CEE Placebo N Age % 45% % 35% >= 75 18% 21% Shumaker et al JAMA 291 (2004), Cumulative Hazard Probable Dementia HR 1.49, 95% CI Estrogen alone Placebo Years Since Randomization

7 Metabolism of steroid hormones; Synthesis of neuroactive Steroids 17-OH Progesterone 11-deoxycortisol Cortisol Allopregnanolone 3α5α-THDOC 3α5α-cortisol

8 Allopregnanolone for anesthesia Bolander et al 1984 Norberg et al 1987 Dose for deep anesthesia Allopregnanolone mg / kg / min

9 The effect of allopregnanolone on sedation and saccadic eye velocity in women measures of GABA A - receptor activation Allopregnanolone i.v. injection (A) mg/kg (B) 0.03 mg/kg (C) mg/kg Sedation score Saccad velocity (deg/sec) Allopregnanolone (nmol/l) A B C Timby et al A B C Occulography Time after first injection, min

10 Anesthetic - effects of steroids Inhibitory 20 Pregnanolone / allopregnanolone 1 Progesterone 0.5 Medroxyprogesterone 0 Levonorgestrel - 0 Norethisterone Excitatory Estradiol Ethinylestradiol Meyerson, Endocrinology 81 (1967) Gyermek, Int J Neuropharmacol. 6 (1967)

11 Genomic and Non-Genomic mechanisms by steroids in the brain After McEwen 1992

12 The GABA- A receptor: A chloride channel Target receptor for GABA, GABA-steroids, Barbiturates, Ethanol and Benzodiazepines

13 GABA-A subunit localization in different parts of the brain (in situ hybridization) α5 is mainly localized in the hippocampus the region for learning and memory. hippocampus α1 α2 α4 α5 α6 β1 β2 γ1 γ2s δ cerebellum Johansson et al, 2007

14 Combating diseases: Brain areas and GABA-A receptor subunits related to treatment platforms for steroid substances 1. Memory and learning disruption Hippocampus α 5 δ 2. Anxiety and mood disturbance 3. Fatigue, sedation and exhaustion Hippocampus amygdale Wide spread α 2 α 4 α 1 β3 δ 4. Depression induced by stress 5. Eating disorders Hypothalamus α 1 α 3 β1 β2 β3 δ γ 2 6. Relapse in alcohol abuse α 6 7. Balance and mobility disorders Cerebellum α 6 β2 δ 8. Epilepsy and excitability disorders α 1 β3 Korpi ER et al Alcohol 2007;41(3):

15 Chronic long-term exposure by all GABA A receptor agonists, give permanent memory and learning impairment, and increase the risk for dementia. e.g. Medroxyprogesterone Shumaker et al. JAMA 289, (2003), Barbiturates Mohammed et al. Drug Alcohol Depend 20 (1987) Benzodiazepines, Barker et al. CNS Drugs 18(2004)37-48 Alcohol Saunders et al. Br J Psychiatry 159 (1991)

16 Effect of long-term benzodiazepine usage on remaining cognitive impairment 6 months after end of therapy. Meta analysis of 10 studies. 284 subjects, 38.7% males. Mean age 42.7 (21 75). Average daily dose in diazepam equivalent = 16.7 mg (SD = 21.1). Mean length of use 8.9 (1-29). Controls: 7 studies used matched healthy controls from general population or anxious control group. 3 used normative data. Barker et al. / Archives of Clinical Neuropsychology 19 (2004)

17 Learning in Morris water maze after allopregnanolone or vehicle given IV 8 and 20 min before swim latency (s) latency Day Johansson et al 2000 Speed (cm/s) speed allo 8 min allo 20 min vehicle 8 min vehicle 20 min Day

18 Stress and memory function Patients were investigated yearly in 3 to 6 years with 24-hour cortisol assessment, and memory performance. They with continuously high adrenal steroid production measured as cortisol received irreversible memory impairment. (Lupien 2005)

19 Rey complex figure memory test in patients with burn out syndrome. Patients performed below expected mean for both immediate and delayed recall. ***P < for both comparisons between groups. Expected mean value = 50. *** *** Sandström et al. / Biological Psychology 69 (2005)

20 Mean ratio for peak steroid levels per unit ACTH after human hcrh injection in patients with Alzheimer's disease (AD; n = 23) and healthy elderly (Controls; n = 19). *p < 0.05; **p < Mean peak steroid concentration per unit ACTH Näsman et al Biol Psychiatry 1996;39(5):311-8.

21 Serum concentrations of allopregnanolone and progesterone during menstrual cycle Nyberg et al 2007 Allopregnanolone, Mean (SD) nmol/l Progesterone, Mean (SD) nmol/l Days in idealizised menstrual cycle Days in idealizised menstrual cycle

22 Allopregnanolone and progesterone during pregnancy Luisi et al, J Clin Endo Metab 2000; 85:

23 Allo - pregnanolone in brain, ng/g (3 x nmol/kg) and Plasma, ng/ml (3 x nmol/l) at Stress Purdy et al PNAS 88(1991)4553

24 Allotetrahydro-cortisol in presence of allopregnanolone increase chloride uptake by the GABA-A receptor. This effect is inhibited by UC1010 (Iso) and other UCcompounds. 3α -OH, 5α -cortisol + 10µM GABA + 1µM Allo A Cl - uptake of control (%) α -OH, 5α -cortisol + 10µM GABA + 1µM Allo + 30µM ISO * * [3α -OH, 5α -cortisol] (µm) Strömberg et al 2005

25 A) Allopregnanolone (ALLO) stimulated Cl - uptake in the presence of 10µM GABA B) UC1010, (ISO), inhibits ALLO stimulated Cl - uptake. Mean Cl - uptake of control (%) 300 A [ISO] = 0 µm Mean Cl - upptake of control (%) [ALLO] = 1000 nm B C Log [ALLO] (nm) Log [ISO] (µm) Lundgren et al 2003

26 Allopregnanolone inhibits hippocampal activity, isoallopregnanolone (UC1010) counteracts the allo effect Difference (%) in population spike (POPSP) amplitude following local application of 6.25 fmol allopregnanolone and/or UC1010 in increasing concentrations (fmol) to CA1 of hippocampus % inhibition of POPSP amplitude Wang et al, Acta Physiol Scand fmol Allo 6.25 fmol UC1010 Allo fmol UC1010 Allo fmol UC1010 Allo fmol UC1010 Allo fmol UC min Time after application

27 UC1011 blocks the GABA-steroid effect on learning in rats in the Morris Water Maze via GABA-steroid antagonism of the GABA A receptor. 120 Latency (s) *** Allopregnanolone Allo:UC1011 UC1011 Vehicle Turkmen et al 2004 Trial Day

28 Allopregnanolone, (ALLO) prolongs the opening of GABA A -receptor at spontaneous GABA release. Ctrl =receptor activated with GABA, ALLO = receptor modulated by GABA+ALLO (5α-pregnan-3α-ol-20-one) On GABA 5α-pregnan-3β-ol-20-one had no effect, Strömberg et al Neuroscience 2006

29 Effect of 3β-OH-5α-pregnane-20-one on Allopregnanolone induced prolongation of GABA-A receptor opening mipsc in cells from preoptic area of rat brain. Strömberg et al. Neuroscience 143 (2006) 73 81

30 Changes in cholinergic release following icv infusions of pregnenolone sulfate (PREGS) and the GABA-steroid allopregnanolone (THPROG) George et al. (2006) Psychopharmacology 186:

31 The End